Li Guang Hua, Akatsuka Shinya, Chew Shan Hwu, Jiang Li, Nishiyama Takahiro, Sakamoto Akihiko, Takahashi Takashi, Futakuchi Mitsuru, Suzuki Hiromu, Sakumi Kunihiko, Nakabeppu Yusaku, Toyokuni Shinya
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Pathol Int. 2017 Nov;67(11):564-574. doi: 10.1111/pin.12598. Epub 2017 Oct 13.
Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P = 0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16 inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.
包括铁过量在内的氧化应激与癌症发生有关。DNA中主要的氧化修饰碱基8-氧代鸟嘌呤的水平通过由OGG1、MUTYH和MTH1编码的三种不同酶维持在非常低的水平。MUTYH的种系双等位基因失活代表一种称为MUTYH相关息肉病的家族性癌症综合征。在这里，我们使用Mutyh基因缺陷小鼠来评估次氮基三乙酸铁（Fe-NTA）诱导的肾癌发生。尽管C57BL/6背景具有抗癌性，但与野生型小鼠（7.1%）相比，反复腹腔注射Fe-NTA在Mutyh基因缺陷小鼠中诱导了高发性肾细胞癌（RCC；26.7%）。Fe-NTA治疗还诱导了肾恶性淋巴瘤，两种基因型在未进行Fe-NTA治疗时均未发生这种情况。Fe-NTA治疗后的无肾肿瘤生存期在两种基因型之间略有差异（P = 0.157）。基于阵列的比较基因组杂交分析显示，在RCC中，4号和12号染色体上存在杂合性缺失且p16未失活；这些结果通过甲基化分析得到证实，并且在基因型之间没有显示出显著差异。淋巴瘤表现出对基因组扩增的偏好。启动子甲基化导致的Dlk1失活可能参与了两种肿瘤的致癌过程。Fe-NTA诱导的小鼠RCCs显示出比大鼠明显更少的基因组畸变，表明存在明显的物种差异。
